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1.  Quantitative correlation between penicillin resistance and beta-lactamase activity specified by the R plasmids R1, R1 bla-45, and RP1 in Escherichia coli K-12. 
A mutant of the R plasmid R1 which synthesizes a beta-lactamase with altered kinetic characteristics was isolated. The level of penicillin resistance specified by this plasmid was correctly predicted from the properties of the wild-type R1 according to a simple theoretical model published by Zimmermann and Rosselet (Antimicrob. Agents Chemother. 12:368--372, 1977). The model also accounts for the high level of penicillin resistance specified by the R plasmid RP1.
PMCID: PMC284074  PMID: 7004346
2.  Growth and antifungal homoazasterol production in Geotrichum flavo-brunneum. 
The growth cycle and production of 15-aza-24-methylene-8, 14-cholestadiene-3 beta-ol (15-azasterol) in Geotrichum flavo-brunneum strain NRRL28804 have been studied. During the growth cycle of this organism, morphological changes were noted which corresponded to changes in the pH of the culture medium. A physiological shift from acid to base production also occurred during the growth cycle. Concomitant with this physiological shift was the synthesis of 15-azasterol. Upon synthesis of this azasterol, variations in the sterol pool were observed. These variations are identical to sterol alterations in susceptible yeast cells exposed to this drug (P. R. Hays, W. D. Neal, and L. W. Parks, Antimicrob. Agents Chemother. 12: 185-191, 1977.) It appears that NRRL28804 avoids growth inhibition from 15-azasterol by confining its production to late in the growth cycle.
PMCID: PMC284097  PMID: 7192535
3.  Influence of chemical modification of N alpha-cocoyl-L-arginine ethyl ester on its hepatitis B surface antigen-inactivating effect. 
We have reported previously that N alpha-cocoyl-L-arginine ethyl ester (CAE) strongly inactivates hepatitis B surface antigen (HBsAg; Sugimoto and Toyoshima, Antimicrob. Agents Chemother. 16:329--332, 1979). Replacement of the L-arginine moiety of CAE by L-lysine did not decrease the HBsAg-inactivating effect of CAE, whereas replacement by some neutral amino acids and L-ornithine decreased it. Esterification of the carboxyl group of N alpha-acyl-L-arginine enhanced its inactivating effect. When the ethyl ester of CAE was converted to an amide group, the effect was appreciably decreased. Modification of the carboxyl group was essential for the inactivation. The effectiveness of N alpha-acyl-L-arginine ethyl ester depends upon the length of the acyl group, with the optimum length for the inactivation of HBsAg being C12 to C14. In addition to CAE, N alpha-lauroyl-L-lysine ethyl ester and N alpha-cocoyl-L-arginine amide were found to be strong inactivators of HBsAg. Significant inactivating effects on HBsAg were not observed in many anionic detergents containing an amino acid. These results suggest that for strongly inactivating HBsAg, a compound should contain a special amino acid, such as L-arginine, and a long acyl group and exhibit a cationic property.
PMCID: PMC284042  PMID: 7447415
4.  Susceptibility testing of clinically isolated anaerobic bacteria by an agar dilution technique. 
Agar dilution minimal inhibitory concentrations (MICs) of penicillin, tetracycline, chloramphenicol, and clindamycin were determined using Wilkens-Chalgren agar for 1,266 clinical isolates of anaerobic bacteria. In addition, a reference strain of Bacteroides fragilis was repeatedly tested and demonstrated the precision of the technique. Fifty-six percent of our Bacteroides melaninogenicus strains were resistant (MIC greater than or equal to 4.0 microgram/ml) to penicillin. Resistance to this antibiotic was also seen among other anaerobes, but the results are more in accord with previous reports. Resistance to tetracycline (MIC greater than or equal to 4.0 microgram/ml) was found in 60% of our isolates. Chloramphenicol proved to be the most effective agent in vitro with only 2.0% of strains resistant (MIC less than or equal to 16 microgram/ml). Only 5% of strains were resistant to clindamycin (MIC greater than or equal to 8.0 microgram/ml), and this included 10 isolates of B. fragilis and 4 of B. melaninogenicus. The incidence of resistance of anaerobic bacteria to these frequently used antibiotics is greater than previous reports and indicates the need for reliable susceptibility testing of anaerobic bacteria.
PMCID: PMC283843  PMID: 6901592
5.  Effect of inoculum size and beta-lactamase production on in vitro activity of new cephalosporins against Haemophilus species. 
Sixty-three strains of Haemophilus species, 38 of which were beta-lactamase producers (37 H. influenzae type b, 1 H. parainfluenzae) and 25 of which were beta-lactamase negative (20 H. influenzae, 5 H. parainfluenzae), were tested for susceptibility to cefoxitin, moxalactam (LY127935) (Lilly), cefsulodin (CGP 7174 E, Ciba), and cefoperazone (T 1551, Pfizer). Cefsulodin was relatively inactive at both low and high inocula. LY127935 and cefoperazone displayed inoculum-dependent bactericidal activity. Cefoxitin displayed little inoculum effect against beta-lactamase-producing strains: 8 and 16 microgram/ml killed at least 90% of those tested at 10(4) and 10(6) colony-forming units per ml, respectively.
PMCID: PMC283797  PMID: 6448575
6.  Comparative susceptibilities of clinical isolates of Serratia marcescens to newer cephalosporins, alone and in combination with various aminoglycosides. 
We examined 100 clinically significant isolates of Serratia marcescens for susceptibility to newer cephalosporin and cephamycin antibiotics, alone and in combination with various aminoglycosides. Moxalactam and cefotaxime were the most effective agents; all isolates were inhibited by 25 and 50 micrograms/ml, respectively. All strains were susceptible to amikacin at concentrations safely achievable in serum, whereas gentamicin, netilmicin, and tobramycin inhibited 63, 63, and 16% of the isolates, respectively. Moxalactam, cefotaxime, and amikacin were active against gentamicin-susceptible and gentamicin-resistant strains. Studies of synergy revealed that moxalactam and cefotaxime, in combination with netilmicin or amikacin, were often synergistic and infrequently antagonistic against cephalothin- and gentamicin-resistant strains. These results suggest that moxalactam and cefotaxime, alone or in combination, may be efficacious in treating infections due to multiply antibiotic-resistant S. marcescens.
PMCID: PMC284070  PMID: 7004344
7.  Tentative interpretive criteria for the diffusion susceptibility test using 30-microgram netilmicin disks. 
The disk diffusion inhibitory zone diameters for 10-microgram and 30-microgram netilmicin disks were correlated with minimum inhibitory concentrations against 471 clinical strains tested in cation-supplemented Mueller-Hinton broth. Regression line and error-rate bounded analysis favored the use of 30-microgram netilmicin disks utilizing zone size breakpoints of greater than or equal to 17 mm to indicate susceptibility (less than or equal to 8 microgram/ml) and less than or equal to 13 mm to indicate resistance (greater than 32 microgram/ml). Significant minor interpretive errors may be expected when testing populations of Pseudomonas that have netilmicin minimum inhibitory concentrations near the intermediate range (16 microgram/ml).
PMCID: PMC284029  PMID: 7425615
8.  Comparative bactericidal effects of azlocillin and ticarcillin against Pseudomonas aeruginosa. 
Azlocillin was relatively ineffective against actively growing cultures of Pseudomonas aeruginosa in tests of bacteriolytic and bactericidal activity in which ticarcillin demonstrated pronounced bactericidal effects over a wide range of concentrations. Microscopic observation showed that azlocillin generally induced the formation of filamentous cells of P. aeruginosa which lysed only slowly, but ticarcillin caused the production of spheroplasts and subsequent rapid lysis. During the course of the bactericidal tests, azlocillin was inactivated, presumably by the beta-lactamase produced by P. aeruginosa, and the filamentous cells resumed normal cell division and growth. In contrast, there was no loss of ticarcillin activity, and there was no evidence of resumption of growth of P. aeruginosa in the presence of ticarcillin. These results suggest that the different bactericidal effects demonstrated by azlocillin and ticarcillin against P. aeruginosa are related primarily to dose-related differences in inhibition of cell wall synthesis and secondarily to the instability of azlocillin to pseudomonal beta-lactamase.
PMCID: PMC283961  PMID: 6774663
9.  Comparative in vitro activity of moxalactam, cefotaxime, cefoperazone, piperacillin, and aminoglycosides against gram-negative bacilli. 
The in vitro activities of four new beta-lactam antimicrobial agents (moxalactam, cefotaxime, cefoperazone, and piperacillin) and the aminoglycosides against 744 recent clinical isolates of facultative gram-negative bacilli were compared simultaneously by the agar dilution method. The major in vitro difference of these newer beta-lactam compounds appeared to be their antipseudomonal activity; cefoperazone was the most active, whereas cefotaxime had the least potency. The aminoglycosides, however, had the most effective in vitro activity on a weight basis against Pseudomonas aeruginosa.
PMCID: PMC284064  PMID: 6255864
10.  Killing of oxacillin-exposed staphylococci in human polymorphonuclear leukocytes. 
Twelve strains of Staphylococcus aureus isolated from patients and two collection strains were grown on membranes placed on agar containing subminimal inhibitory concentrations of oxacillin. Clusters of staphylococci held together by thick cross walls resulted. These organisms, as well as the same strains grown in the same way on drug-free medium (control), were eluted from the membranes and were incubated with human polymorphonuclear leukocytes (PMNs) from various donors. Phagocytosis was comparable for both staphylococci exposed to oxacillin and control staphylococci, but the killing effect was different. The staphylococci grown on membranes in the presence of oxacillin were less susceptible to killing than the control staphylococci, but the killing effect was different. The staphylococci grown on membranes in the presence of oxacillin were less susceptible to killing than the control staphylococci. After 0.5 and 1 h of incubation with PMNs, the killing rates for oxacillin-grown versus control staphylococci were 52 and 70% and 65 and 85%, respectively (P < 0.01). After 2 and 3 h of incubation, the killing was similar. Most clusters of staphylococci contain a few individual cells that are located in the center of the cluster and are surrounded by other staphylococci; therefore, they are protected from adverse agents in the environment. This could explain why the phagocytized clusters are less susceptible than control staphylococci to the killing effect of PMNs during the first hour of incubation. Oxacillin does not penetrate into PMNs and in the absence of the drug the cross walls lyse, liberating the constituent staphylococci. This coincides with the increase in the percentage of cluster killing by PMNs after 2 and 3 h of incubation.
PMCID: PMC284095  PMID: 7447433
11.  Clinical and Pharmacokinetic Evaluation of Parenteral Cefoxitin in Infants and Children 
Thirty-two infants and children ranging in age from 3 to 151 months (mean, 26 months) were treated with parenteral cefoxitin (150 mg/kg per day). Ten patients with isolates of Haemophilus influenzae (six with cellulitis, two with arthritis, and two with mastoiditis), four with Staphylococcus aureus (one with lymphadenitis, one with septicemia, and two with abscess), and three patients with Streptococcus pneumoniae (one each with cellulitis, abscess, and arthritis), were clinically and bacteriologically cured by therapy. Two additional patients with septic arthritis and facial cellulitis developed meningitis with H. influenzae type b and S. pneumoniae, respectively. Minimal inhibitory and bactericidal concentrations were ≤5 μg/ml for 15 isolates. Minimal bactericidal concentrations were >20 μg/ml for one strain of S. aureus and one of H. influenzae type b. The mean peak serum levels were 81.9 and 68.5 μg/ml 15 min after intravenous or intramuscular doses, respectively. The mean elimination half-lives were 42.4 and 40.1 min after intravenous or intramuscular doses, respectively. The mean volumes of distribution were 5,540 and 4,760 ml after intravenous and intramuscular doses, respectively. Mean plasma clearance was 242 and 257 ml/min per m2 after intravenous and intramuscular doses, respectively. Therapy was discontinued in one patient because of neutropenia, which resolved after cefoxitin was stopped. Eosinophilia and transiently elevated liver function tests occurred in eight and six patients, respectively. These data indicate that cefoxitin may be an effective treatment for infections due to susceptible bacteria in the dosage tested, but its use may be limited because of the occurrence of meningitis during therapy in some patients.
PMCID: PMC283850  PMID: 7396456
12.  Activity of mecillinam alone and in combination with other beta-lactam antibiotics. 
The in vitro activities of mecillinam, ticarcillin, cefamandole, and cefoxitin, singly and in all possible combinations, against 53 clinical isolates were studied by a checkerboard method of determining minimal inhibitory concentrations. For selected representative strains, bactericidal activity was determined by minimal bactericidal concentrations and killing curves. Mecillinam was the least active antibiotic against gram-positive cocci, Pseudomonas aeruginosa, and Bacteroides fragilis and the most active against Enterobacteriaceae. Reproducibility of mecillinam minimal inhibitory concentrations for susceptible Enterobacteriaceae was often poor, however, due to minor variations in inoculum size. When mecillinam resistance was observed with Enterobacteriaceae, partial inhibition could be demonstrated at concentrations below minimal inhibitory concentrations, and bacterial cells were consistently ovoid or round; under those conditions the addition of a second study antibiotic resulted in marked synergistic inhibition and killing which was independent of inoculum size and susceptibility to the second antibiotic. In contrast, synergy with mecillinam against mecillinam-susceptible strains or with other antibiotic combinations against any species was not consistently observed.
PMCID: PMC352987  PMID: 6263179
13.  Purification and biochemical properties of beta-lactamase produced by Proteus rettgeri. 
beta-Lactamase produced by Proteus rettgeri was found to be a typical cephalosporin beta-lactamase on the basis of its substrate hydrolysis profile. The enzyme activity was enhanced by prior treatment with an inducer. The enzyme was purified 166-fold by carboxymethyl-Sephadex column chromatography which indicated that its molecular weight was 42,000 +/- 2,000 and its isoelectric point was 8.7. Cefoperazone, cefoxitin, cefusulodin, cefmetazole, cefotaxime, 6059-S, FK749, YM-09330, carbenicillin, and cloxacillin were stable to this enzyme and possessed the function of competitive inhibition, as shown by their affinity for the beta-lactamase. The enzyme activity was inhibited by iodine, p-chloromerburibenzoate, and HG2+ ion. Clavulanic acid and CP-45899 displayed poor inhibitory activity toward this enzyme. The optimal pH was 8.0, and the optimal temperature was 50 degrees C.
PMCID: PMC284076  PMID: 6969578
14.  Activity of beta-lactamase produced by Bacteroides fragilis against newly introduced cephalosporins. 
The purified beta-lactamase from Bacteroides fragilis hydrolyzed newly introduced cephalosporins including cefuroxime and HR 756, and was inhibited by 7 alpha-methoxylated cephalosporins such as 6059-S and YM09330.
PMCID: PMC283862  PMID: 6967295
15.  Comparative study of piperacillin, ticarcillin, and carbenicillin pharmacokinetics. 
Piperacillin, ticarcillin, and carbenicillin were administered intravenously to 10 healthy volunteers in a three-way, crossover study. The pharmacokinetics of the three drugs were in general quite similar. The peak serum concentration of piperacillin achieved at the end of a 30-min intravenous infusion was 63.5 +/- 27.6 microgram/ml. During the first 8 h, 67.5% of the dose of piperacillin was excreted in the urine, and the urinary concentration was extremely high. All three penicillins had high volumes of distribution. The serum half-life of the beta elimination phase of carbenicillin was lower than that of either piperacillin or ticarcillin. The volunteers experienced no adverse reactions from the administration of the drugs.
PMCID: PMC283839  PMID: 6446878
16.  Moxalactam (LY127935), a new semisynthetic 1-oxa-beta-lactam antibiotic with remarkable antimicrobial activity: in vitro comparison with cefamandole and tobramycin. 
Moxalactam (LY127935) exhibited greater in vitro activity than cefamandole and tobramycin against clinical isolates of Enterobacteriaceae, Aeromonas hydrophila, and Pseudomonas maltophilia. The activities of the three drugs against other microorganisms were as follows: for staphylococci, cefamandole = tobramycin greater than moxalactam; for streptococci, cefamandole greater than moxalactam greater than tobramycin; and for Pseudomonas aeruginosa, tobramycin greater than moxalactam greater than cefamandole. Moxalactam also demonstrated significant activity against the Bacteroides fragilis group and other anaerobes. Moxalactam was comparable to cefotaxime (HR756) in its inhibition of cephalothin-resistant and aminoglycoside-resistant clinical isolates.
PMCID: PMC283866  PMID: 6446880
17.  Comparison of in vitro activity of moxalactam (LY127935) with cefazolin, amikacin, tobramycin, carbenicillin, piperacillin, and ticarcillin against 420 blood culture isolates. 
To compare the in vitro activity of moxalactam (LY127935), a new broad-spectrum antimicrobial agent, with cefazolin, amikacin, tobramycin, carbenicillin, piperacillin, and ticarcillin, each drug was tested against 420 bacterial isolates from the blood of septic patients. Standard broth dilution methods were used to determine minimum inhibitory and bactericidal concentrations. LY127935 was as active as the aminoglycosides against aerobic gram-negative organisms, including Pseudomonas aeruginosa, and was at least 10-fold more active than the other beta-lactam agents against these bacteria. LY127935 was the most active agent tested against Bacteroides fragilis; its activity against all other anaerobic bacteria and Staphylococcus aureus was similar to those of the other agents tested. All streptococci, however, grew at higher concentrations of LY127935 than any other drug, and Streptococcus faecalis and Listeria monocytogenes were not inhibited at the highest concentration tested (minimum inhibitory concentration, > 64 microgram/ml). Although a greater proportion of blood culture isolates were susceptible to LY127935 than to any other drug tested, LY127935 does not have a sufficiently broad spectrum of in vitro activity to be recommended safely alone for empirical treatment of sepsis of unknown etiology.
PMCID: PMC283801  PMID: 6448577
18.  Comparative in vitro activity of 1-oxa-beta-lactam (LY127935) and cefoperazone with other beta-lactam antibiotics against anaerobic bacteria. 
The in vitro activity of 1-oxa-beta-lactam (LY127935), cefoperazone (T-1551), cefuroxime, cefsulodin, cefaclor, cefotaxime, and cefoxitin on 85 anaerobic clinical isolates (30 Bacteroides, 30 Clostridium, 25 Peptococcaceae) was simultaneously determined by the agar dilution test in two different media, Brucella Agar (Difco Laboratories) and Wilkins-Chalgren agar. In Wilkins-Chalgren agar, 90% of Bacteroides were inhibited by (micrograms per milliliter): LY127935, 0.5; T-1551, 64; cefoxitin or cefuroxime, 8; cefsulodin or cefotaxime, 32; and cefaclor, 128. All Clostridia were inhibited in Wilkins-Chalgren by (micrograms per milliliter): LY127935, 4; T-1551, 2; cefoxitin, 6; cefuroxime, 0.12; cefsulodin, 0.5; cefaclor, 1; and cefotaxime, 8. All Peptococccaceae were inhibited by T-1551, cefsulodin or cefotaxime at 4 microgram/ml and by cefoxitin or cefuroxime at 1 to 2 microgram/ml. With cefaclor at 8 microgram/ml, 92% of strains were inhibited, and LY127935 at 16 microgram/ml only inhibited 64% of strains. LY127935 was the most active of the antibiotics tested against Bacteroides, showing good activity against Clostridia and poor activity on Peptococcaceae, whereas T-1551 was more active against Peptococccaceae and had similar activity against Clostridia and poor activity on Bacteroides. There are no significant differences between minimal inhibitory concentrations obtained in Brucella Agar and those obtained in Wilkins-Chalgren.
PMCID: PMC283746  PMID: 6247966
19.  Comparison of cotrimoxazole, ampicillin, and chloramphenicol in treatment of experimental Haemophilus influenzae type B meningitis. 
To evaluate cotrimoxazole in the treatment of bacterial meningitis, we compared its action with that of ampicillin and chloramphenicol in experimental Haemophilus influenzae type b meningitis. Both trimethoprim and sulfamethoxazole penetrated well into the cerebrospinal fluid of infected rabbits, reaching 40 and 26%, respectively, of their simultaneous serum levels. Levels measured 30 and 60 min after intravenous injection exceeded the minimum inhibitory concentration of this combination for H. influenzae by 10- to 100-fold. The mean ratio of trimethoprim to sulfamethoxazole in cerebrospinal fluid was 1:22. Cotrimoxazole was as effective as ampicillin in therapy of beta-lactamase-negative H. influenzae meningitis and as effective as chloramphenicol for a beta-lactamase positive strain. These findings corroborate favorable preliminary clinical experience reported by others and indicate that cotrimoxazole deserves further study in the therapy of bacterial meningitis.
PMCID: PMC283724  PMID: 6965442
20.  Isolation of an ampicillin-resistant, non-beta-lactamase-producing strain of Haemophilus influenzae. 
A 79-year-old female developed endocarditis and meningitis due to an ampicillin-resistant, non-beta-lactamase-producing strain of Haemophilus influenzae. Carbenicillin and gentamicin therapy resulted in bacteriological and clinical cure. The mechanism of resistance of ampicillin-resistant, non-beta-lactamase-producing strains of H. influenzae is unknown.
PMCID: PMC283729  PMID: 6965443
21.  In Vitro Antibacterial Activity of AM-715, a New Nalidixic Acid Analog 
AM-715 [1-ethyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-3-quinolinecarboxylic acid] is a new nalidixic acid analog. AM-715 has a broad spectrum of antibacterial activity against gram-positive and gram-negative bacteria. The antibacterial activity of AM-715 was greater than those of pipemidic acid and nalidixic acid. AM-715 had higher antibacterial activity against Pseudomonas aeruginosa than did gentamicin. Most nalidixic acid-resistant bacteria were susceptible to AM-715, and cross-resistance was not observed between AM-715 and various antibiotics. The minimal concentration of AM-715 required to inhibit the growth of 75% of the total number of clinical isolates was as follows: Escherichia coli, 0.04 μg/ml; Klebsiella pneumoniae, 0.1 μg/ml; Serratia marcescens, 0.88 μg/ml; Enterobacter spp., 0.076 μg/ml; Staphylococcus aureus, 1.10 μg/ml; P. aeruginosa, 0.38 μg/ml; and nalidixic acid-resistant strains of gram-negative bacteria, 0.62 μg/ml. AM-715 at minimal inhibitory concentrations or at slightly higher concentrations had bactericidal activity against various species of bacteria. The effect of inoculum sizes on minimal inhibitory concentrations and minimal bactericidal concentrations of AM-715 against gram-negative bacteria was smaller than on those of pipemidic acid and nalidixic acid. The dose-response curve of AM-715 indicated a steep gradient, and the 50% inhibited doses of AM-715 were 0.014 μg/ml against E. coli ML4707 and 0.21 μg/ml against P. aeruginosa NC-5.
PMCID: PMC283741  PMID: 6446258
22.  Tentative interpretive standards for disk susceptibility tests with moxalactam (LY127935). 
Moxalactam (LY127935; 6059-S) is a new beta-lactam antibiotic. We propose tentative zone standards for agar diffusion susceptibility tests with 30-microgram disks. The final selection of minimal inhibitory concentration breakpoints for definition of resistant and susceptible categories must await clinical experience with this drug. Some of the clinical questions to be answered are defined. A moderately susceptible (intermediate) category is proposed for those strains with minimal inhibitory concentrations of 16 or 32 microgram/ml (zones 15 to 22 mm in diameter). Strains with minimal inhibitory concentrations of greater than or equal to 64 microgram/ml are considered resistant, and those with minimal inhibitory concentrations of less than or equal to 8 microgram/ml are considered susceptible. Tests with 30-microgram disks did not satisfactorily separate strains with minimal inhibitory concentrations of 8 microgram/ml from strains requiring < 2 microgram/ml for inhibition, because the regression line became parabolic at concentrations of 2 microgram/ml and below. However, the disk tests were satisfactory for categorizing isolates into the above-described susceptible, moderately susceptible (intermediate), and resistant categories.
PMCID: PMC284081  PMID: 6449905
23.  In vitro activity of cefoperazone against nonfermenters and Aeromonas hydrophila. 
The in vitro activity of cefoperazone against 380 strains (33 species and unnamed groups) of nonferenters and 20 strains of Aeromonas hydrophila was studied by a microdilution method of determining minimal inhibitory concentrations. For comparison, the activities of ampicillin, ticarcillin, and cefamandole were simultaneously studied. Cefoperazone was the most active drug against Pseudomonas sp., Achromobacter xylosoxidans, Flavobacterium meningosepticum. Flavobacterium sp. (group IIb), Group IVc biotype 2, Group Ve, and Aeromonas hydrophila. Against other organisms it was equivalent in activity to or less active than comparative antibiotics. The only organisms which were usually resistant to 128 microgram of cefoperazone per ml were strains of Flavobacterium odoratum and Group IIk biotype 1.
PMCID: PMC284028  PMID: 6448581
24.  5-epi-Sisomicin and 5-epi-Gentamicin B: substrates for aminoglycoside-modifying enzymes that retain activity against aminoglycoside-resistant bacteria. 
A number of bacterial strains, each possessing a different aminoglycoside-modifying enzyme, were examined for susceptibility to sisomicin and gentamicin B and the semisynthetic derivatives 5-epi-sisomicin and 5-epi-gentamicin B. Although strains possessing AAC (6') or APH(3') enzymes were equally resistant to the 5-epi-compounds, those possessing AAC(3)-I, ANT(2"), or AAC(2') enzymes were much more sensitive to the 5-epi derivatives. Analysis of partially purified aminoglycoside-modifying enzymes from the strains showed that the 5-epi compounds were substrates even for those enzymes found in susceptible strains [AAC(3)-I, ANT(2"), and AAC(2')]. However, a more detailed study of the enzymes showed that they had much increased Km values for the 5-epi derivatives; the 5-epi compounds were much less effectively modified than the parent antibiotics. This confirms and extends the notion that enzymatic modification of aminoglycosides is not in itself sufficient to confer resistance to the drugs, but also that the modification must be efficient, as reflected in the Km values.
PMCID: PMC283878  PMID: 6967296
25.  Prospective, randomized trial of netilmicin and amikacin, with emphasis on eighth-nerve toxicity. 
The toxicity of netilmicin was compared with that of amikacin in a randomized, prospective trial in 90 adults with a variety of serious gram-negative infections. There was no instance of antibiotic-related nephrotoxicity in the group given amikacin and only one instance in the group given netilmicin. Cochlear toxicity, as measured by a change in audiogram, occurred in 4/14 (28.5%) of the amikacin recipients and 3/19 (15.8%) of the netilmicin recipients. Vestibular toxicity, as determined by a change in ice-water calorics, was noted in 3/16 (19%) of the amikacin-treated patients and 0/15 of the netilmicin-treated individuals. Despite the trend toward lesser ototoxicity with netilmicin, the differences between the drugs were not statistically significant. There was, however, a significant association between male sex and the development of ototoxicity. Although many patients could not be evaluated for efficacy, there did not appear to be any difference in the therapeutic activity of the two drugs.
PMCID: PMC283857  PMID: 6994638

Results 1-25 (377)